Background: Acetaminophen (paracetamol) is commonly used to lower the temperature of patients with fever suspected to be causeed by an infection in both homes across the world and the hospital. There are, however, opposing theories to the utility of decreasing fever in these situations. One side argues that fever places “additional physiological stress on patients,” who are already ill (Young 2015). Removing this source of increased metabolic demand would allow the body to allocate additional resources to fighting infection, respiratory function etc. On the other hand, fever may “enhance immune-cell function” and inhibit further growth and spread of an infecting pathogen (Young 2015). From a simple evolutionary standpoint, fever, which entails a significant cost likely evolved and persists because it benefits the host. To date we don’t have high-level evidence that acetaminophen treatment of fever due to probable infection is beneficial, ineffective, or harmful.

The HEAT Trial

What Study are we Discussing?

What They Did:

Prospective, Parallel-Group, Blinded Randomized Controlled Trial

Randomly assigned 700 ICU patients aged 16 years of age or older with fever (≥38°C) and known or suspected infection in 1:1 ratio to receive 1g IV acetaminophen vs placebo (5% dextrose in water) every 6hrs until:

ICU discharge

Resolution of fever

Cessation of Antimicrobial Therapy

Death

Patients Excluded: See table S1 (BELOW)

Exclusion Criteria

AST or ALT >5x the upper limit of normal, or bilirubin > 2x the upper limit of normal, or any other contraindication to 4g acetaminophen per day

A requirement for ongoing use of non-steroidal anti-inflammatory drugs (in excess of low dose 300mg/day aspirin)

Admission to ICU following a cardiac arrest which is currently being treated with therapeutic hypothermia or where a need for therapeutic hypothermia is anticipated

Hyperthermic syndromes including heat stroke; current biochemical evidence of thyrotoxicosis (thyroid function tests are not required before recruitment into the trial unless clinically indicated); malignant hyperthermia, neuroleptic malignant syndrome, or other drug-induced hyperthermia

Limitation of therapy order or aggressive treatment is deemed unsuitable

Moribund; death is perceived to be imminent (within 24 hours)

Rhabdomyolysis deemed by the treating clinician to be clinically significant

Transferred from another ICU where they spent >12hrs and fulfilled all inclusion criteria while there

Pregnancy

Previously enrolled or previously eligible for enrollment during the current ICU admission but not enrolled in the study (i.e. patients who were not enrolled within 12hrs of onset of fever in association with satisfying other eligibility criteria may not be enrolled at a later point in the ICU admission)

Outcomes:

Primary: ICU-free days (days alive and free from the need for intensive care) from randomization to day 28 (if the patient died during the study, they were counted as 0 “ICU-free days”)

Secondary:

All-cause mortality at day 28 and 90

Survival time (Number of days alive) from randomization until day 90

ICU and hospital length of stay

Hospital-free days, Days free from mechanical ventilation

Days free from inotropes or vasopressors

Days free from renal replacement therapy

Days in the ICU that were free from support

Results:

700 patients (10 withdrew consent and not included in analysis) in 23 adult medical-surgical ICUS in Australia and New Zealand

Acetaminophen Arm: 346 patients

Placebo Arm: 344 patients

Number of ICU-free days to day 28

Acetaminophen Group: 23 days

Placebo Group: 22 days

Not Statistically Significant p = 0.07

Mortality by day 90

Acetaminophen Group: 55/345 patients (15.9%)

Placebo Group: 57/344 patients (16.6%)

RR 0.96 (95% CI 0.66 – 1.39; p = 0.84)

Strengths:

Study asks an important question with an important outcome

Only large, multicenter study of its kind

Randomization and blinding well performed

Excellent follow up (98.6%)

All analyses conducted prior to unmasking the study-group assignments

Limitations:

Protocol violations were high in both the acetaminophen (30%) and placebo (28%) groups

Open-label acetaminophen was administered to 30% of patients in both arms

Acetaminophen use before randomization or after ICU discharge was not recorded

33% of patients received acetaminophen after the course of the study drug had been completed

It is unclear if these results can be extrapolated to the use of oral acetaminophen

Median duration of the study drug was short

Discussion:

Acetaminophen was associated with shorter ICU stay than placebo in survivors and longer ICU stay among non-survivors, but there was no statistically significant difference between groups with respect to 28d mortality, 90d mortality, or survival time to day 90

Author Conclusion: Early administration of acetaminophen to treat fever due to probably infection did not affect the number of ICU-free days.

Clinical Take Home Point: Fever need not always be treated in patients with suspected infectious causes. It appears reasonable to give acetaminophen to patients in whom the fever is causing distress but it is similarly reasonable to withhold it in patients who are not distressed.